[unreadable] Collapsing glomerulopathy (CG), a clinically aggressive and therapeutically resistant proliferative podocytopathy, develops predominantly in T helper type 1 (Th1)-polarizing disorders. Despite this strong clinical correlate in CG and knowledge of the pathogenic role of Th1 responses in other proliferative parenchymal renal lesions, little research has been done to determine whether Th1 effectors may precipitate or exacerbate CG. Based on leading results generated by us and others during the first two years of research under K08 DK065498 which suggest an important, targetable contribution from the pleotropic Th1 effector molecule, tumor necrosis factor-alpha (TNF-(), to the proliferative parenchymal injury in CG, this associated R03 proposal will undertake three new specific aims. In Specific Aim 1, we will determine whether soluble TNF-( is a mitogen for mouse and human glomerular visceral epithelial cells by engaging TNF receptors and inducing the expression of G1-phase cyclins. TNF-( is now known to directly promote the proliferation of several different epithelial cell-types in vitro and in vivo; however, the phenotypic response of glomerular visceral epithelial cells to soluble TNF-( is poorly understood. In Specific Aim 2, we will develop a manipulatable murine system to determine if the renal CD11c+ dendritic cell network serves as a dominant source of intra-renal TNF-( that may challenge glomeruli in CG. This system will also allow us to study the potential role of the renal dendritic cell network in other aspects of the pathogenesis of CG. In Specific Aim 3, we will determine whether second generation pharmacologic cyclin-dependent kinase / glycogen synthase kinase 3 (CDK/GSK-3) inhibitors, novel drugs for the treatment of CG, suppress TNF-( expression and induce IL-10 expression in activated renal CD11c+ dendritic cells. Inhibition of GSK-3 can determine whether pro- versus anti-inflammatory cytokines are produced by dendritic cells; we will determine if these drugs induce a similar phenotypic drug response from activated renal dendritic cells. These adjoining specific aims to K08 DK065498 will identify novel pathways whereby pro-inflammatory Th1 responses and, in particular, TNF-(, may contribute to the pathogenesis of CG and further our understanding of the integrative therapeutic properties of pharmacologic CDK/GSK-3 inhibitors. The outcomes from these specific aims will bolster the development of funding and research initiatives beyond K08 DK065498. The R03 award would also facilitate the publication of research-in-progress and provide ongoing support for technical assistance established during the first-half of K08 DK065498. [unreadable] [unreadable]